Postoperative radiotherapy for completely resected thymoma and thymic carcinoma: A systematic review and meta-analysis

Background The role of postoperative radiotherapy (PORT) after complete tumor resection in patients with thymoma or thymic carcinoma remains controversial. We performed a meta-analysis to identify groups that would benefit from PORT. Methods Multiple scientific databases were systematically searched for studies comparing overall survival (OS) and/or disease-free survival (DFS) between PORT and surgery alone in patients with completely resected thymomas or thymic carcinomas until April 10, 2024. A random-effects model was used for the statistical analysis. Results A total of 31 studies with 10543 patients were included (17 studies involving 4763 patients with thymoma, seven studies involving 1045 patients with thymic carcinoma, and seven studies involving 4735 patients with mixed histological types). Notably, PORT significantly prolonged OS (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.59–0.91) and DFS (HR = 0.62, 95% CI: 0.43–0.89). Similar results were also observed when the multivariate-adjusted HRs were used as the measure of effect (OS: HR = 0.60, 95% CI: 0.43–0.83; DFS: HR = 0.48, 95% CI: 0.29–0.79). In subgroup analyses, PORT was associated with a longer OS and DFS for thymoma (HR = 0.73, 95% CI: 0.56–0.96 and HR = 0.65, 95% CI: 0.46–0.93), thymic carcinoma (HR = 0.72, 95% CI: 0.49–1.07 and HR = 0.38, 95% CI: 0.19–0.77), and stage 3–4 disease (HR = 0.50, 95% CI: 0.34–0.74 and HR = 0.44, 95% CI: 0.27–0.70), but not for stage 2 disease (HR = 0.81, 95% CI: 0.55–1.19 and HR = 0.97, 95% CI: 0.51–1.83). Conclusions PORT is likely to improve OS and DFS in patients with completely resected stage 3–4 thymoma or thymic carcinoma; however, the value of PORT for stage 2 disease requires further evaluation in large-scale studies.


Introduction
Thymic epithelial tumors (TETs) are rare tumors with an incidence of 3.2 cases per million [1], and are classified as thymoma, thymic carcinoma, and thymic neuroendocrine tumors.Surgery is the mainstay of treatment for resectable thymoma or thymic carcinoma, and complete tumor resection is the most significant predictor of outcomes [2,3].Postoperative radiotherapy (PORT) is considered important for incompletely resected cases.However, the value of PORT in patients with complete tumor resection remains controversial owing to the lack of randomized controlled trials and conflicting results from observational studies  and meta-analyses [35][36][37][38].
In fact, completely resected TETs are heterogeneous.Notably, PORT has been associated with improved survival in patients with stage 3 but not stage 2 thymoma [31].Patients with thymoma with histologic subtype B benefited more from PORT than those with histologic subtype A [19], and PORT using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) had a higher 5-year OS rate than two-dimensional radiation therapy (2D-RT) [11].These findings suggest that the benefit of PORT appears to be affected by the clinicopathological features of patients, and differences in these features in individual studies may account for the inconsistent findings.To date, few studies have specifically addressed the role of PORT based on the clinicopathological features of patients.Therefore, individualized assessment of the value of PORT remains essential.
In light of these issues, we conducted a comprehensive meta-analysis of the currently available evidence on completely resected TETs to clarify the subgroup of patients who could benefit from PORT.

Literature search
This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [39].Two authors (HT and YJ) independently searched PubMed, Embase, Cochrane Library, and Web of Science databases as of April 10, 2024.The detailed search strategies are shown in S1 Table.Furthermore, references in the relevant reviews were manually checked.

Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) prospective or retrospective study design; (2) study population comprising patients with completely resected (R0) thymoma and/or thymic carcinoma; (3) interventions comprising PORT and surgery alone; (4) outcomes including overall survival (OS), disease-free survival (DFS), and/or recurrence-free survival (RFS); and (5) publication in English.Studies that included a small proportion of patients with incomplete tumor resection (<10%) were also considered eligible.In case of overlap of patient data among the studies, the study with the most comprehensive data was selected.

Data extraction and quality assessment
Two authors (HT and YJ) independently extracted the following data from each article: name of the first author; year of publication; period of recruitment; study design; median follow-up time; sample size in each group; and hazard ratios (HRs) with 95% confidence intervals (CIs) for OS, DFS, and RFS.
The Newcastle-Ottawa scale [40] was used to evaluate the quality of the studies, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) [41] was used to assess the quality of the evidence.

Statistical analysis
This meta-analysis was conducted using R software (version 3.5.3,R Foundation for Statistical Computing) via the meta-package using the random-effects model.The outcomes of interest were OS, DFS, and RFS, which are presented as HRs with 95% CIs.Notably, HRs with 95% CIs were calculated using Kaplan-Meier curves [42] when not directly reported in the studies.The I 2 test was used to investigate heterogeneity.Univariate and multivariate meta-regression analyses were performed to assess sources of heterogeneity.Subgroup analyses were conducted according to the histological type, stage, year of publication, and region.The robustness of the results was evaluated using sensitivity analysis.Publication bias was estimated using funnel plots and Egger's test [43].

Literature search and study selection
Notably, 2321 records were found during the initial search.After removing duplicates, 781 records were identified.Of these, 610 publications were excluded after reviewing the titles and abstracts, and the remaining 171 articles underwent a full-text assessment.Fig 1 shows the study selection process and reasons for exclusion.Finally, 31 retrospective studies  with 10543 patients (4945 who underwent PORT and 5598 who underwent surgery alone), were included in this meta-analysis.Among them, there were 17 studies involving 4763 patients with thymoma, seven studies involving 1045 patients with thymic carcinoma, and seven studies involving 4735 patients with mixed histological types.The Masaoka or Masaoka-Koga staging system was used in all studies.Six studies [17-19, 22, 27, 29] included a small number of patients with incomplete tumor resection (<10% in each study).Most studies did not provide detailed information regarding the surgical method, RT technique, RT dose, or neoadjuvant or adjuvant chemotherapy.Characteristics of the included studies are listed in Table 1.

Assessment of study and publication bias
Three studies [6,14,22] were rated with a score of 5, and the other studies had a score of �6 (S2 Table ).No significant publication bias was observed in OS (Egger's test, P = 0.61) or PFS (Egger's test, P = 0.15).Funnel plots are shown in S1 Fig.

PORT vs. surgery alone on OS, DFS, and RFS
Compared to surgery alone, PORT was associated with a significantly longer OS (HR = 0.73, 95% CI: 0.59-0.91,I 2 = 55%) ( Twelve and seven studies reported multivariate-adjusted HRs for OS and DFS, respectively.When these adjusted HRs were used as the measure of effect, PORT also significantly

Cumulative meta-analysis of PORT vs. surgery alone on OS and DFS
Because the included studies had a time span of >20 years, we conducted a cumulative metaanalysis in which the studies were added in the order of publication year.We found that the OS benefit of PORT was generally observed in publications since 2015, but not in most publications before 2015 (Fig 4).The cumulative meta-analysis of DFS showed similar results (S3 Fig).

Subgroup analysis of PORT vs. surgery alone on OS and DFS
The results of the subgroup analyses are summarized in Fig 5 , and the forest plot for each result can be found in S4-S11 Figs.

The GRADE assessment
The results of the GRADE assessment are presented in S3 Table .The evidence for OS, DFS, and RFS showed low GRADE ratings.Regarding the subgroup analyses, the evidence for OS and/or PFS had moderate GRADE ratings in the subgroups of adjusted HRs, publications before 2015, non-Asian populations, thymoma, and thymic carcinoma and low GRADE ratings in the other subgroups.

Meta-regression analysis
Univariate and multivariate meta-regression analyses were conducted to investigate whether age, sex, year of publication, region, histological type, and stage were sources of heterogeneity (S4 Table ).Multivariate meta-regression showed that publication year and stage were significantly associated with OS heterogeneity (P = 0.03 and P = 0.007, respectively).

Sensitivity analysis
Sensitivity analysis for OS and DFS showed that omitting one study at a time did not significantly alter the results (S12 Fig).

Discussion
This meta-analysis comprehensively assessed the role of PORT in patients with completely resected thymoma and thymic carcinoma.Our results showed that PORT significantly improved OS and DFS compared to surgery alone.Similar results were observed when multivariate-adjusted HRs were used as a measure of the effect.However, in the subgroup analysis, OS and PFS benefits with PORT were observed in stage 3-4 disease, but not in stage 2 disease.Although the current National Comprehensive Cancer Network guidelines recommend the use of PORT for completely resected stage 2-4 thymoma and thymic carcinoma [44], few clinical studies have demonstrated the survival benefit of PORT in patients with stage 2 disease.The heterogeneity of stage 2 tumors may affect the efficacy of PORT.In a study using the International Thymic Malignancy Interest Group database [19], PORT significantly prolonged OS for completely resected stage 2 thymomas, and histologic subtypes B1-B3 were associated with the greatest OS benefit.Another study based on the National Cancer Data Base [23] showed significantly improved OS with PORT in patients with stage 2B thymoma, but not in those with stage 2A thymoma.These findings suggest that PORT may be suitable for selected stage 2 patients, such as those with extensive capsular invasion (stage 2B) and/or aggressive histological subtypes (B1-3).However, these hypotheses must be validated in large-scale studies.
Given that thymic carcinoma is more aggressive, PORT should be more useful in patients with this histological type.In two single-institution studies [16,29], PORT achieved better OS and DFS in patients with stage 1-3 thymic carcinoma after complete resection.Significantly improved DFS and a trend towards better OS with PORT in patients with thymic carcinoma were also observed in our meta-analysis.Nevertheless, two studies based on the Japanese Association for Research of the Thymus [20] and the Surveillance, Epidemiology, and End Results [24] databases did not demonstrate an OS benefit of PORT for completely resected thymic carcinoma.Notably, the use of adjuvant chemotherapy in individual studies was inconsistent.Some studies have demonstrated the survival benefits of adjuvant chemotherapy for completely resected thymic carcinoma [29,45].In a study by Tang et al. [30], adjuvant chemotherapy was associated with improved OS in thymic carcinoma with superior vena cava or innominate vein invasion.In another study by Gao et al. [45], the most common failure was distant metastasis in patients with stage 3-4 thymic carcinoma after complete resection, and PORT combined with adjuvant chemotherapy (POCRT) was an independent predictor of improved DFS.These results indicate that PORT may be insufficient, and POCRT should be considered for completely resected thymic carcinomas, especially in patients with advancedstage disease.
Considering the patients recruited in studies spanning more than six decades, we conducted a cumulative meta-analysis according to the year of publication.We found that publications since 2015 generally reported significantly better OS in the PORT group, whereas most publications before 2015 did not.Subgroup analysis according to the year of publication also showed significantly improved OS and DFS with PORT in studies published after 2015, but not in studies published before 2015.One possible reason for these findings is the increased use of modern RT techniques, such as 3D-RT or IMRT, over time.Fan et al. [11] demonstrated a higher 5-year OS (100% vs. 86.9%)and lower regional recurrence (3.6% vs. 32%) rates with PORT using 3D-CRT/IMRT vs. 2D-RT in patients with completely resected stage 3 thymoma.Although detailed information on RT techniques was not provided in most of the studies included in our meta-analysis, more patients were likely to receive 3D-RT/IMRT in studies published after 2015 than in those published before 2015 according to the study period.
Overall, our results support the use of PORT in a subgroup of patients with stage 3-4 thymoma or thymic carcinoma.Although significantly positive results were not observed for stage 2 disease, some selected cases (such as stage 2B and histological subtype B) seemed to benefit from PORT.The use of 3D-CRT/IMRT is possibly an important factor associated with improved survival after PORT.Despite requiring further validation, these findings will be helpful to clinicians in developing individual treatment strategies for this patient population.
Differing from our results, two previously published meta-analyses [36,38] found an OS benefit of PORT in patients with resected stage 2 thymomas or thymic carcinomas.However, the meta-analysis by Zhou et al. [36] (14 included studies) included many patients with incomplete or unclear resection statuses.Although a meta-analysis by Tateishi et al. [38] used adjusted HRs as a measure of effect, only five studies were included in their meta-analysis, with only two studies on stage 2 disease.Therefore, drawing conclusions regarding the benefits of PORT in patients with stage 2 tumors remains difficult.
The strengths of the present study are the large number of studies and sample size, and the fact that almost all of the patients included in the study underwent complete resection.In addition, considering the imbalance in background characteristics between the treatment groups, adjusted HRs were used as a measure of effect to validate the results.Moreover, comprehensive subgroup analyses were performed.All of these would be helpful in increasing the statistical power of our analyses.
However, our study has some limitations.First, all data in our meta-analysis were collected from retrospective studies, which have inherent limitations such as selection biases.Second, the heterogeneity was high for OS and DFS.The results of the meta-regression analyses indicated that disease stage was significantly associated with heterogeneity.In addition, histological subtype, adjuvant chemotherapy, RT technique, and surgical method may also be confounding factors.Third, adverse events could not be assessed because most included studies did not provide this information.Finally, some HRs were calculated using the Kaplan-Meier curve, which might result in an error in comparison with the direct calculation from the raw data.

Conclusions
Our results suggest that PORT is likely to improve OS and DFS in patients with completely resected stage 3-4 thymoma or thymic carcinoma; however, the value of PORT for stage 2 disease requires further evaluation in large-scale studies.These findings should be validated in future large-scale studies.In addition, the roles of POCRT and PORT using modern RT techniques should be assessed in future studies.